CAREER: Intramolecular Chaperone Encoded pH Sensors in Pro-protein Convertases

Oregon Health & Science University, Portland OR

Investigators

Abstract

After folding in the endoplasmic reticulum (ER), several proteases sequentially transit through a proton gradient maintained by series of distinct cellular compartments of the secretory pathway en route to their final destination. During this transit, proteases regulate their activation by recognizing the compartment-specific proton concentration by a poorly understood mechanism. The goal of this project is to advance understanding of this mechanism using pro-protein convertases, a family of eukaryotic serine proteases. Pro-protein convertases sense the compartment-specific proton gradient through histidine pH sensors encoded within N-terminal intramolecular chaperone domains. This project will employ biochemical, structural, computational and cell biological approaches to (i) identify the structural determinants of these pH sensors, (ii) establish the mechanism by which the pH sensor functions in pro-protein convertases, and (iii) understand how sequence variations allow for differential regulation of pro-protein convertases. The results from experiments described in this project will provide insights into the general mechanisms by which the compartment-specific proton gradient regulates biological functions of eukaryotic proteins. Broader impacts: This CAREER development project will provide a unique educational opportunity for undergraduate and graduate students, particularly those from underrepresented minorities, to actively participate in a research project that integrates biophysics, biochemistry, computational and cell biology. New coursework will be created to train students on how to quantify and establish mechanisms for contemporary issues in biological sciences using multidisciplinary approaches. The participants will synergistically join an educational outreach effort in the department to bring current scientific investigation to local middle and high schools. Through summer laboratory employment, high school students will gain research experience and scientific confidence, while they play integral roles in the development of modern technologies. These activities will enhance Oregon Health and Science University's efforts towards the recruitment and retention of underrepresented students and encourage diversity for future applicants.